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The tumor microenvironment is an altered milieu that imposes multiple selective pressures leading to the survival and dissemination of aggressive and fit tumor cell subpopulations. How pre-tumoral and tumoral cells respond to changes in their microenvironment will determine the subsequent evolution of the tumor. In this study, we have subjected pre-tumoral and tumoral cells to coverslip-induced hypoxia, which recapitulates the intracellular hypoxia and extracellular acidification characteristic of the early tumor microenvironment, and we have used a combination of quantitative phase microscopy and epifluorescence to analyze diverse cellular responses to this altered environment. In normoxia, tumor cells showed differences in nuclear organization, as evidenced by decreased numbers of HP1 foci, and in hypoxia major changes in nuclear architecture were observed, with tumor cells significantly increasing the number of high dry mass density foci in the nucleus compared to pre-tumoral and non-tumoral cells. Conversely, compared to pre-tumoral and normal cells, mitochondrial ATP levels decayed markedly in tumor cells in hypoxia, whereas the activation of executioner caspases increased only in tumor cells in this condition. Therefore, in terms of cellular organization, metabolic changes and activation of cell death processes, tumor cells showed more dramatic responses to an altered microenvironment than their pre-tumoral and normal counterparts, responses which in turn could play fundamental roles in shaping future tumor development. [ABSTRACT FROM AUTHOR]